1. Field of the Invention
The present invention relates generally to methods and systems for preparing and using radiation delivery devices and combination radiation and drug delivery devices, such as beads, seeds, particles, rods, gels, and the like. In particular, the present invention relates to methods and systems for preparing and using absorbable radiation delivery devices and combination radiation and drug delivery devices having core elements which will be resorbed in tissue over time.
2. Description of the Background Art
A number of techniques have been proposed to treat tumor growth. Brachytherapy relies on implanting a radiation source to provide localized treatment, as contrasted, for example, with treating a site from a distance by external beam radiation. In prostate brachytherapy, radiation delivered by small "seeds" placed very close to the area being treated are used. Such placement minimizes the chance of affecting nearby tissue, while still delivering adequate radiation to destroy diseased cells.
Ultrasound-guided prostate brachytherapy, also called "interstitial brachytherapy" or simply a "seed implant," is exemplary of minimally invasive brachytherapy techniques. It does not require a hospital stay and typically has no long term side effects. Initially, an ultrasound "volume study" is performed to measure the prostate gland and plan the treatment. A few weeks later, radioactive seeds are inserted using a needle under ultrasound guidance directly into the prostate. The procedure takes about an hour and, after a short recovery period, the patient can usually go home.
While successful in many patients, brachytherapy relies on deposition of metallic seeds that remain in place after treatment. Should the initial treatment be less than fully effective, the continuing presence of the seeds can preclude or restrict a clinician's ability to subsequently image and/or re-treat a tumor.
The preparation of conventional brachytherapy devices is problematic in a number of respects. In particular, the devices are usually fabricated from metal alloys that are subsequently irradiated or plated to become radioactive. The devices so prepared have a limited shelf life. For devices fabricated at a central facility, distribution and inventory maintenance become significant problems. Further, devices fabricated from metal allows are not absorbable. That is, once the device has been fabricated, e.g. by irradiation or plating, its useful life is limited and its metallic core will not degrade. The permanence of the device core is a particular problem in subsequent disease monitoring and treatment. A metallic core that remains at the treatment site can both interfere with radiographic and other imaging of the region (thus making disease monitoring difficult) and prevent certain follow-up therapies.
Biodegradable radioactive implant materials have been made for diagnostic and imaging purposes. For example, a radioisotope may be bound to a biodegradable polymeric matrix where the purpose is usually to provide for controlled release of the radioactive material over time. Such biodegradable radioactive materials are generally not useful for brachytherapy since they release the radioactive material rather than localize it at the desired treatment site.
Radiopharmaceuticals composed of antibodies, peptides, and other localizing substances have been made and injected directly into tumors for radiotherapeutic purposes. During such direct injections a portion of the radiolabeled antibodies, peptides, and the like bind to the tumor. However, a substantial amount of these radiopharmaceuticals are washed out of the tumor by normal clearance mechanisms. The result of this washout is a decreased dose to the tumor and an increased dose to normal organs such as bone marrow, the liver, and kidneys. A number of radio-colloids have been prepared from Re-186, Re-188, Y-90, P-32, Ho-166, Sm-153, and the like, and have been used to treat tumors of cavities such as metastatic pleural effusion, malignant pericardial effusion, peritoneal metastasis cavity and the like. These colloids are delivered by use of an in-dwelling catheter and are designed to provide a thin film of radioactive colloid throughout the cavity. Thus, radiocolloids are useful for treating tumors, tumor metastasis, and diseases of cavities, and irradiate both tumor cells and normal cells lining the cavity. Such colloids have not been used in concert with biodegradable matrices. Some of the colloids, including Re-188 sulfur colloid have been used-to treat liver tumors by injecting them into the vasculature of the liver. This approach, however, can result in considerable shunting of the radioactive materials to the normal lung.
The use of biodegradable or bioerodible materials to provide sustained or controlled release of chemotherapeutic or other drugs, including bioactive drugs, has been known for a number of years. Biodegradable implants for the controlled release of hormones, such as contraceptive hormones, were developed over twenty years ago, and have been used as birth control devices. Biodegradable or bioerodible materials employed for controlled release of drugs include polyanhydrides, polyglycolic acid, polylactic/polyglycolic acid copolymers, polyhydroxybutyrate-valerate and other aliphatic polyesters, among a wide variety of polymeric substrates employed for this purpose. Many of these materials have been characterized by inconsistent drug release kinetics.
For many applications, such as biodegradable implants for controlled release of contraceptive implants, the site of implantation is unrelated to the drug target, and implantation is simply employed as a mechanism for sustained delivery. In some applications, biodegradable polymer implants have been used to directly deliver chemotherapeutic agents to a desired treatment side. For example, polymer implants which release the cancer chemotherapeutic dug carmustine have been used as implants in the surgical cavity created when a brain tumor is removed. As the wafer erodes, it releases the cancer chemotherapeutic drug directly to the tumor site in high concentrations over an extended period of time. (Jampel H D, Koya P, Leong K, Quigley H A. In vitro release of hydrophobic drugs from polyanhydride disks. Ophthalmic Surg 1991; 22:676-680.)
The synergistic effect of combined radiation and chemotherapy has long been appreciated, and is a standard modality of cancer therapy. Prior art methods have frequently employed systemic chemotherapy, where chemotherapy drugs are administered intravenously, orally or by other systemic means, and external radiotherapy is employed, such as external beam radiation. In one instance, biodegradable polymer implants for the treatment of cancer, containing the cancer chemotherapeutic drug carmustine, have been used with concurrent external beam radiation, and found to increase survival in patients with metastatic brain tumors. (Ewend M G, Williams J A, Tabassi K, et al. Local delivery of chemotherapy and concurrent external beam radiotherapy prolongs survival in metastatic brain tumor models. Cancer Res 1996; 56(22):5217-5223) Conventional systemically administered chemotherapeutic agents have also been used in conjunction with implanted brachytherapy devices.
For these reasons, it would be desirable to provide improved methods and devices for the delivery of radioactivity and also chemotherapeutic, bioactive or other drugs to patients for therapeutic purposes. In particular, it would be desirable to provide improved delivery devices which deliver both local radiation and local chemotherapeutic or bioactive drugs, and are degradable after implantation so that they largely or completely disappear from the treatment region over time. The structure or core of such devices, however, should have sufficient permanence or persistence so that the bound radioisotope or other radioactive source material will remain localized at the site of implantation at all times while the emitted radiation remains significant, i.e., above some defined threshold level. It would be further desirable to provide fabrication methods and techniques which permit the construction of delivery devices having a variety of forms, including both relatively large devices, such as seeds, pellets, and other delivery devices of the type commonly used in brachytherapy of tumors and other proliferative diseases, as well as beads, particles, microparticles, and other small forms which can be utilized in other types of treatment. It would be further desirable to provide devices wherein the chemotherapeutic or bioactive drug release rate can be determined prior to use of the device in a patient, so that the drug release rate can be correlated to the radiotherapy rates.
The preparation of biodegradable radioactive materials is described in U.S. Pat. Nos. 5,256,765 and 5,194,581 and PCT application WO 91/06286. Other biodegradable implantable materials, some of which have been used in drug delivery systems, are described in U.S. Pat. Nos. 5,656,297; 5,543,158; 5,484,584; 4,897,268; 4,883,666; 4,832,686; and 3,976,071. U.S. Pat. No. 5,876,452 describes biodegradable polymeric material, such as polyanhydries and aliphatic polyesters, providing substantially continuous release of bioactive drugs, including bi-phasic release of bioactive drugs. U.S. Pat. No. 5,338,770 describes methods and materials for coating biomedical devices and implants with poly(ethylene oxide) chains suitable for covalent attachment of bioactive molecules intended to counteract blood-material incompatibility. U.S. Pat. No. 5,463,010 describes membranes, including polymerized aliphatic hydrocyclosiloxane monomers, for use in coating biomedical devices and implants, and suitable for use as a substrate for covalent attachment of other molecules. A variety of U.S. patents describe various methods for labeling of substrates, typically peptides, proteins and the like, with radioactive metal ions, such as use of DTPA chelates in U.S. Pat. Nos. 4,479,930 and 4,668,503; U.S. Pat. No. 5,371,184, in which a chelate ligand is disclosed for labeling hirudin receptor-specific peptides; U.S. Pat. No. 4,732,864, in which the use of metallothionein or metallothionein fragments conjugated to biologically active molecules is disclosed; U.S. Pat. No. 5,225,180, in which technetium-99 m labeling of peptides containing at least two cysteine residues capable of forming a disulfide bond through reduction of the disulfide is disclosed; U.S. Pat. No. 5,443,953, in which a variety of conjugates for radioisotopes are disclosed; U.S. Pat. No. 5,376,356, in which a variety of methods of radiolabling and conjugates are disclosed; U.S. Pat. No. 5,382,654, in which a variety of bifunctional chelates are disclosed; and U.S. Pat. No. 5,464,934, in which a method of metal chelation, using amino acid sequences that are capable of forming metal complexes, is disclosed. U.S. Pat. Nos. 5,277,893; 5,102,990; and 5,078,985 each describe proteins containing one or more disulfide bonds which are radiolabeled with radionuclides, including technetium and rhenium for use in diagnosis and treatment. U.S. patent application Ser. No. 09/098,072; filed Jun. 16, 1998, describes methods useful in the present invention for coating polymeric and other materials. The full disclosures of each of these patents and pending application are incorporated herein by reference.